Gestational ethanol effects on dorsal striatal function and associated behaviors

妊娠期乙醇对背侧纹状体功能和相关行为的影响

• 批准号: 8810270
• 负责人: Verginia Carmella Cuzon Carlson
• 金额: $ 24.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810270
• 关键词: 2-arachidonylglycerol; Adult; Age-Months; Alcohol consumption; Alcohols; Basal Ganglia; Behavior; Behavioral; Biological; Cannabinoids; Cells; Centers for Disease Control and Prevention (U.S.); Congenital Abnormality; Control Animal; Corpus striatum structure; Data; Decision Making; Defect; Dorsal; Electrophysiology (science); Embryo; Endocannabinoids; Enzyme Inhibition; Enzymes; Ethanol; Exposure to; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Functional disorder; Glutamates; Human; Human Development; Hyperactive behavior; Impairment; Impulsivity; Individual; Infant; Interneurons; Lateral; Lead; Learning; Long-Term Survivors; Manuscripts; Memory impairment; Mentors; Molecular; Motor; Movement; Mus; Neurons; Operant Conditioning; Output; Parvalbumins; Phase; Play; Pregnancy; Production; Psyche structure; Reporting; Research; Role; Signal Transduction; Somatostatin; Specificity; Symptoms; Synapses; System; Technology; Testing; Viral; Western Blotting; Woman; alcohol effect; anandamide; binge drinking; classical conditioning; conditioning; disability; drinking; habit learning; inhibitor/antagonist; lipoprotein lipase; motor deficit; mouse model; neural circuit; neurotransmission; optogenetics; partial recovery; patch clamp; postnatal; receptor; research study; transmission process; vapor

The objective of the proposed research plan is to investigate the effects of gestational ethanol (EtOH) exposure on dorsal striatal circuitry that contribute to some of the behavioral abnormalities, such as impaired decision making, increased impulsivity, and motor deficits that observed in Fetal Alcohol Spectrum Disorder (FASD). Using a mouse model, we will expose individuals via a vapor chamber to ethanol throughout the embryonic and early postnatal period in order to mimic the three trimesters of human development (gestational EtOH) and examine the disposition of dorsal striatal circuitry and associated behaviors during adulthood. Preliminary findings to date indicate that in adult mice that were exposed to gestational EtOH display decreased GABAergic transmission in the dorsal lateral striatum (DLS) that appears to involve increased modulation by endocannabinoids. We observed no gestational EtOH-induced effect of glutamatergic transmission. Gestational EtOH also impairs habit learning; a type of associative instrumental conditioning that involves the DLS. 1 will determine the mechanisms underlying these gestational EtOH effects by accomplishing the following specific aims: 1) Determine the synaptic specificity of aberrant GABAergic microcircuits in the DLS of mice exposed to gestational EtOH. To accomplish this 1 propose viral, optogenetic, and electrophysiological experiments to examine the three major GABAergic synapses onto striatal medium spiny neurons (MSNs), those formed by parvalbumin interneurons, those formed by other MSNs, and those formed by low-threshold spiking somatostatin interneurons. 2) Rescue of gestational EtOH exposure on associative learning and striatal neurotransmission: possible avenues for treatment. Using the information gained in specific aim 1,1 will use pharmacological agents to decrease endocannabinoid tone to rescue the impaired habit learning and GABAergic neurotransmission.Taken together, the completion of this project will lay the groundwork for assessing how disruptions of the GABAergic microcircuitry of the striatum underlie many of the behavioral abnormalities seen in FASD and suggest approaches to compensate for these effects.

拟议研究计划的目的是研究妊娠乙醇 (EtOH) 的影响 背侧纹状体回路的暴露会导致一些行为异常，例如受损 在胎儿酒精谱系障碍中观察到的决策、冲动增加和运动缺陷 （胎儿酒精谱系障碍）。使用小鼠模型，我们将通过均热板将个体暴露在乙醇中 胚胎和产后早期，以模仿人类发育的三个三个月 （妊娠乙醇）并检查背侧纹状体电路的配置和相关行为 成年期。迄今为止的初步研究结果表明，在暴露于妊娠期乙醇的成年小鼠中 显示背外侧纹状体 (DLS) 中的 GABA 能传输减少，这似乎涉及 增加内源性大麻素的调节。我们没有观察到妊娠期乙醇诱导的影响 谷氨酸能传递。妊娠期乙醇也会损害习惯学习；一种联想工​​具 涉及 DLS 的调节。 1 将确定这些妊娠乙醇的潜在机制 通过实现以下具体目标来实现效果：1）确定异常的突触特异性 暴露于妊娠 EtOH 的小鼠 DLS 中的 GABA 微电路。为了实现这一目标 1 建议病毒式传播， 光遗传学和电生理学实验来检查三个主要的 GABA 突触 纹状体中型多棘神经元 (MSN)，由小白蛋白中间神经元形成的神经元，由其他神经元形成的神经元 MSN，以及由低阈值尖峰生长抑素中间神经元形成的 MSN。 2) 妊娠乙醇的拯救 接触联想学习和纹状体神经传递：可能的治疗途径。使用 在具体目标 1,1 中获得的信息将使用药物来降低内源性大麻素的张力 拯救受损的习惯学习和GABA能神经传递。总之，完成这个 该项目将为评估纹状体 GABA 微电路的破坏如何奠定基础 FASD 中许多行为异常的根源，并提出了补偿方法 这些影响。